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3,262,935 QUATERNARY AMMONIUM ENOLATES F PSEUDU-ACIDS OF THE KETONICTYPE Reginald L. Wakeman, Philadelphia, Pa., and E Griliin Shay, BelleMead, N.J., assignors, by mesne assignments, to Millmaster Onyxijorporation, New York, N.Y., a corporation of Delaware No Drawing.Filed June 15, 1964, Ser. No. 375,352 6 Claims. (Cl. 260-286) The objectof the present invention is the preparation of microbiologically activecompounds by reaction of certain quaternary ammonium salts withalkali-metal salts of pseudo-acids of the ketonic type.

The products of this invention conform, in general, to the followingstructure:

2 0 R-( J=C"-R I wherein Z is the cation of a microbiologically activequaternary ammonium compound; R is an alkyl or a halogenated alkylgroup; R is hydrogen, a halogen or an acyl group; and R" is an alkyl oran alkoxy group.

Typical of these pseudo-acids are 2,4 pentanedione; 3- bromo-2,4pentanedione; 1-phenyl-l,3 butanedione; 3-acetyl-2,4-pentanedione;1-trifluoro-2,4 pen tanedione; ethyl acetoacetate and the like. They arecharacterized in that they have an active hydrogen in the alpha positionand in that they require an .appreciable length of time to io-nize.

Typical examples of the quaternary ammonium compounds which may be usedin this invention are the alkyl trimethyl ammonium chlorides,alkyl-benzyl trimethyl ammonium chlorides, alkyl dimethyl benzylammonium chlorides, alkyl dimethyl menaphthyl ammonium chlorides, alkyldimethyl substituted-benzyl ammonium chlorides in which the benzylradical is substituted with one or more side chains containing from 1 to5 carbon atoms such, for example, as methyl, dimethyl, ethyl and thelike and in which the carbon atoms may all be in the same or differentside chains or in which the benzyl radical bears one, two or morehalogen atoms such as chlorine or bromine, alkyl pyridinium chlorides,alkyl isoquinolinium chlorides and bromides, alkyl lower-alkylpyrrolidinium chlorides, alkyl lower-alkyl morpholinium chlorides in allof which the alkyl group may have from 8 to 22 carbon atoms and thelower alkyl group may have from 1 to 4 carbon atoms and alkyl phenoxyethoxy ethyl dimethyl benzyl ammonium chloride in which the alkylradical may be iso-octyl or nonyl and in which the phenyl radical may,if desired, be substituted by a methyl radical. Various other analogs ofthese quaternaries may also be employed such, for example, as cetyldimethyl ethyl ammonium bromide or oleyl dimethyl ethyl ammoniumbromide.

In g neral, the quaternary ammonium compounds useful in this inventionare the higher alkyl quaternary ammonium hydroxides, halides (chloridesand bromides), sulfates, methosulfates and the like possessing thefollowing formula:

R X l\ R! RI! R!!! where R is an alkyl or alkar-alkyl radical containingfrom 8 to 22 carbon atoms or an alkyl phenoxy ethoxy ethyl radical inwhich R is an alkyl radical containing from 8 to 9 carbon atoms and inwhich the phenyl radical may be substituted by a methyl group; R and R"are methyl or ethyl radicals or members of a heterocyclic ring systemsuch as pyridine, isoquinoline, pyrrolidine and morsalt or unreactedmaterials. The solvent,

LiiiiliCE 3,262,935 I July 26, 1966 pholine; R' is a methyl radical or abenzyl group or a substituted-benzyl group such, for example, as amonochlorobenzyl radical or a dichlorobenzyl radical or mixture thereofor .a methyl benzyl, dimethyl benzyl, ethyl benzyl, diethyl benzyl,isopropyl benzyl, tertiary butyl benzyl or another benzyl radicalcontaining from 1 to 5 carbon atoms as side chains, either as-a singleside chain or a multiplicity of side chains including mixtures thereofor a menaphthyl group of hydrogenated menaphthyl group. When R and R aremembers of a morpholine or pyrrolidine ring, R is a methyl, ethyl,propyl or butyl group. When R and R are members of an unsaturatedheterocyclic ring such as pyridine or isoquinoline, R' is the sameradical as R. X in the above formula corresponds to a halide radicalsuch as chloride, bromide or iodide or to any other water-soluble anionsuch as methosulfate.

In general, we prefer nium compounds which least with respect to to usesuch quaternary ammohave a phenol coefiicient of at both Staphylococcusmureus and Salmonella typhosa at 20 C. when determined by the standardmethod given in the Official Methods of Analysis of the Association ofOflicial Agricultural Chemists, ninth edition (1960), page 63 et seq.

The compounds of this invention may be prepared by dissolving thepseudo-acid in question in dilute caustic soda solution to form thesodium salt and mixing this with a solution of a quaternary ammoniumsalt.

After thorough mixing, the organic product layer is separated from theaqueous layer (as with a separatory funnel) since two distinct phasesare formed. Separation may be facilitated by the addition of an organicsolvent immiscible with water. The product layer may be washed withwater to remove any residual by-product if any, may be evaporated andthe product air or vacuum dried to a paste, wax, oil or solid.

It is not necessary to use an aqueous medium. Any solvent or solventmixture in which the starting materials are soluble will besatisfactory. Non-aqueous solvents facilitate the separation of byproduct inorganic salt and reduce the need for vacuum drying to get ananhydrous product. When a non-aqueous medium is employed, it is usuallynecessary to add a small amount of water to facilitate ionic reaction.

The product may be used, if desired, without drying since any entrappedwater is irrelevant to the mircrobiological activity of the compounds.In other applications, removal of water may be essential for reasons notrelated to biological activity.

An alternative method for the preparation of compounds especiallyapplicable tothe treatment of fabric, ropes, net, woven and non-wovenfabric and reticulated or convoluted materials involves a two-stepprocess. In the first step, the material is passed through a bathcontaining the anionic moiety. Excess solution is removed by methodswell known to those skilled in the art. The treated material is thenpassed through a second bath wherein the concentration of quaternaryammonium compound is such that the material pickup will result in anequivalent amount of quaternary ammonium compound reacting with theanionic moiety, depositing the product in the most intimate way on thesuriiace and in the interstices, eonvolutions and reticulations of thematerial.

The method of adjustment of solution concentration to achieve therequired pickup is well known to those skilled in the art. The order oftreatment may be reversed without affecting the biological activity ordurability of the product on the material. The products of thisinvention may be formulated as water dispersions by dissolving them in awater miscible organic solvent such as SEARCH ROGM b acetone or methanoland diluting with water or by dissolving them in emulsifiable oils such,for example, as sulfonated castor oil or pine oil and diluting withwater. In preparing aqueous dispersions, emulsifying agents such, forexample, as ethylene oxide condensates of alkyl phenols may be used withor without organic solvents.

It is surprising that the compounds of this invention exhibit highmicrobiological activity despite their relative insolubilityin water.Because of their unusual combination of physical and microbiologicalproperties, they can be used to impart laundry-resistant anti-microbialcharacteristics to textiles. They can also be used as the active agentin antimildew finishes for textiles which are resistant to leaching withwater.

Although the compounds have low water solubility, they are compatiblewith various organic solvents, plasticizers and high molecular weightcompounds. Consequently, they may be incorporated as anti-microbialagents in synthetic resins and plastics. The compounds are compatiblewith natural and synthetic rubber latices. Therefore, they may be usedto prepare bacteriostatic films and molded objects deposited from suchlatices.

The compounds can be incorporated into cutting and grinding fluidswithout precipitation. Also, they blend well with non-ionic and anionicsurf-ace active agents. In

such compositions they retain their microbiological activity.

(1) Mildewproofing fabric, canvas, ropes, textiles, awnings, sails,tenting and other woven and nonwoven reticulated materials.

Paint mildewstats.

Iet plane fuel additive to control growth of microorganisms.

Odor preservative agents for clothes and shoes.

Mildew retardant and odor suppressant for shoes and other leatherproducts.

Topical antiseptics.

Antidandruff agents.

Disinfection agents for hair and gut of man and beast.

Bacteriostatic furniture dressing.

Surface finishes for stone, plaster, tile, cement, brick and otherinorganic building materials to retard growth of microorganisms, fungi,mold and algae.

Wool preservative.

Plant and tree spray to combat fungi.

Antimycotic agents for soap Wrappers.

Self-sanitizing brushes.

Mildewpr-oofing agent in and on plastic and film.

Mildewproofing of cellulosics, cardboard, fibreboard, paper and cordage.

Contact biostat for application to film, waxes and cloth to preservecheese, meats and vegetables and other food products.

Algal inhibition, especially on surfaces and in solution where lowfoaming is desirable.

Paper pulp slime control.

Sanitizing agent for rug, carpet, curtains.

Egg preservation.

Adhesive preservation.

Preservation of latex paints.

Preservation of metal-working compounds.

Additives for soap and for both anionic and nonionic detergents inliquid, bar, powder, bead,

solution and other forms to impart bacteriostatic and fungistaticproperties thereto.

(26) Bacteriostatic agents for household laundry softeners.

(27) Algastat and bacteriostat in recirculated water for cooling towers,air conditioners and humidifiers.

(28) Bacteriostat and alg-astat for flood Waters and brines used insecondary oil recovery.

(29) Fungistat for seed and soil treatment against damping-off.

The microbiological activity of our compounds has been evaluated formicrobiological stasis by the Standard Tube Dilution Test, the techniquefor which is common knowledge to those skilled in the art. A Difco BactoCSMA broth #0826 was used in the study. This test is used to determinethe lowest concentration of microbiologically active compounds whichwill inhibit the growth of the organisms in question. For a wide rangeof applications, the inhibition of growth rather than outright kill issatisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of theCSMA broth in a test tube which is then sterilized in an autoclave. Onecc. solution of the microbiologically active compound at an appropriateconcentration is added to the test tube which is then inoculated with0.1 cc. of a twenty-four hour old culture of the organism under study.The test tube is then incubated at 37 C. for forty-eight hours andobserved for bacterial growth.

The same procedure is followed for fungi. In such tests, however, thetubes are incubated for fourteen days at a temperature suitable foroptimum fungal growth, usually 25 C.

The invention is illustrated by, but not limited to, the followingexamples:

Example I A 10% solution of 1-phenyl-1,3 butanedione sodium salt wasprepared by dissolving the ketone in sodium hydroxide solution.

An aliquot of this solution containing 0.0326 molecular weight of thecompound was mixed with vigorous agitation with a chemically equivalentamount of a 10% aqueous solution of a commercial grade of alkyl dimethylethyl-benzyl ammonium chloride (Millmaster Onyx Corporations ETC-471 inwhich the alkyl distribution is C12, 30% C 17% C 3% C The mixture wasseparated in a separatory funnel and the organic product layer wasremoved and vacuum dried. Sixteen grams of the alkyl dimethylethyl-benzyl ammonium salt of 1-phenyl-l,3 butanedione was recovered asa yellow oil or 95% of the theoretical yield.

When tested by the Standard Tube Dilution Method described above, thisproduct gave the following values for static dilution vs.:

Staphylococcus aureus l0 Salmonella typhosa l0- Aspergz'llus niger 10'Example II An aliquot of the solution of the sodium salt of 1-phenyl-1,3 butanedione of Example I containing 0.0326 molecular weightof the compound was vigorously agitated while adding a chemicallyequivalent amount of a 10% solution of a commercial grade of alkyldimethyl benzyl ammonium chloride (Millmaster Onyx Corporations ETC-824in which the alkyl distribution is C 30% C 5% C 5% C The mixture alongwith a little benzene was transferred to a separatory funnel wherein twophases separated. The organic product layer was removed and vacuumdried. The alkyl dimethyl benzyl ammonium salt of 1-phenyl-l,3butanedlone was recovered in 91% of the theoretical yield as a yellowliquid.

When tested by the Standard Tube Dilution Method described above, theproduct gave the following values for static dilution vs.:

Staphylococcus aureus 10- Salmonella typhosa 10 Aspergillus niger 10*Example [II An aliquot of the solution of the sodium salt of 1-phenyl-1,3 butanedione of Example I containing 0.0326 molecular weightof the compound was agitated vigorously while adding a chemicallyequivalent amount of a 10% aqueous-alcohol solution of a commercialgrade of alkyl isoquinolinium bromide (Millmaster Onyx CorporationsIsothan Q-75 in which the alkyl distribution is 50% C 30% C 17% C 3% CThe mixture was heated to evaporate the alcohol, cooled and transferredalong with a little benzene to a separatory funnel wherein it separatedinto two phases. The organic product layer was removed and vacuum driedto a dark brown liquid in 97% yield of the alkyl isoquinolinium salt ofl-phenyl-1,3 butanedione.

When tested by the Standard Tube Dilution Method described above, thisproduct gave the following values for static dilution vs.:

Staphylococcus aureus l- Salmonella typhosa l0 Aspergillus niger ExampleIV A solution of the sodium salt of 2,4-pentanedione containing 0.050molecular weight of the compound was reacted with a chemicallyequivalent amount of an aqueousalcohoi solution of a commercial grade ofdodecyl dimethyl menaphthyl ammonium chloride (Millmaster OnyxCorporations ETC-1100). The alcohol was evaporated off and the organicproduct layer was removed and vacuum dried. The dodecyl dimethylmenaphthyl ammonium salt of 2,4-pentanedione as a solid was recovered inthe theoretical yield.

Example V Ethyl acetoacetate was dissolved in dilute aqueous sodiumhydroxide to form the sodium salt. An aliquot of this solutioncontaining 0.240 molecular weight was reacted with the chemicallyequivalent 'amount of the dodecyl menaphthyl ammonium chloride ofExample IV. Benzene was added and dried to yield the dodecyl mewherein Zis the cation of a quaternary ammonium compound having a phenolcoefficient of at least with respect to Staphylococcus aureus andSalmonella lyphosa at 20 C. and having at least one alkyl group of 8 to22 carbon atoms on the quaternary nitrogen; R is selected from the groupof alkyl and halogenated alkyl; R is selected from the group ofhydrogen, halogen, carboxyalkyl and carboxyaryl; and R is selected fromthe group of alkyl and alkoxy.

References Cited by the Examiner UNITED STATES PATENTS 1/1955 Newcomer167-22 OTHER REFERENCES Schales, 0.: Arch Biochem. Biophys, vol. 34,page 59, 61, 62 (1951).

Schwartz: Surface Active Agents and Detergents, vol. II, Interscience,1958, page 222.

Snyder, H. R.: J. Am. Chem. Soc., vol. 66, page 200-4 1944) ALEX MAZEL,Primary Examiner.

NICHOLAS S. RIZZO, DONALD G. DAUS,

Assistant Examiners.

3. ALKYL ISOQUINOLINIUM ENOLATE OF 1-PHENYL-1,3,-BUTANEDIONE.
 6. AQUATERNARY AMMONIUM KETONIC ENOLATE HAVING THE STRUCTURE: